Molecular mechanism in regulation of the intramembrane proteases

• Project/Area Number: 23657082
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Functional biochemistry
• Research Institution: Tohoku University
• Principal Investigator: FUTAI Eugene 東北大学, (連合)農学研究科(研究院), 准教授 (90447459)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2013: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2012: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2011: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 酵素 / プロテアーゼ / 脳・神経 / 認知症 / 酵母

Research Abstract

Since intramenbrane proteases possess these active sites buried in the lipid bilayer, it is difficult to purify and measure their activities. We introduced human gamma-secretase complex in yeast and succeeded in measuring its activity in vitro with the yeast microsomes. In this research, we utilized the reconstition system and analyzed the enzymatic character of the gamma-secretase. We found the relationship between proteolytic activities and subunit composition, and we screened the modulator of the protease activities from lipids and natural compounds. Malfunction of gamma-secretase leads to Alzheimer's disease. We would like to expand our research to the treatment of the disease.

Research Products

• [Journal Article] CTF1-51, a truncated carboxyl-terminal fragment of amyloid precursor protein, suppresses the effects of A β -lowering γ-secretase modulators (2012)
  • Author(s): Watahiki, H., Yagishita, S., Futai, E. & Ishiura, S
  • Journal Title: Neurosci. Lett Volume: 526 Pages: 96-99
  • Peer Reviewed
• [Journal Article] Localization of mature neprylysin in lipid rafts (2012)
  • Author(s): Sato, K., Tanabe, C., Yoneyama, Y., Watahiki, H., Zhao, Y., Yagishita, S., Ebina, M., Suo, S., Futai, E., Murata, M. & Ishiura, S
  • Journal Title: J. Neurosci. Res Volume: 90 Pages: 870-877
  • Peer Reviewed
• [Journal Article] Tumor suppressor cell adhesion molecule 1 (CADM1) is cleaved by a disintegrin and metalloprotease 10 (ADAM10) and subsequently cleaved by γ -secretase complex (2012)
  • Author(s): Nagara, Y., Hagiyama, M., Hatano, N., Futai, E., Suo, S., Takaoka, Y., Murakami, Y., Ito, A. & Ishiura, S
  • Journal Title: Biochem. Biophys. Res. Commun Volume: 417 Pages: 462-467
  • Peer Reviewed
• [Journal Article] Localization of mature neprilysin in lipid rafts. (2012)
  • Author(s): Sato K, Tanabe C, Yonemura Y, Watahiki H, Zhao Y, Yagishita S, Ebina M, Suo S, Futai E, Murata M, Ishiura S.
  • Journal Title: J. Neurosci. Res. Volume: 90 Issue: 4 Pages: 870-877
  • DOI: 10.1002/jnr.22796
  • Peer Reviewed
• [Journal Article] CTF1-51, a truncated carboxyl-terminal fragment of amyloid precursor protein, suppresses the effects of Aβ42-lowering γ-secretase modulators. (2012)
  • Author(s): Watahiki H, Yagishita S, Futai E, Ishiura S.
  • Journal Title: Neurosci. Lett. Volume: 526 Issue: 2 Pages: 96-99
  • DOI: 10.1016/j.neulet.2012.08.029
  • Peer Reviewed
• [Journal Article] Comparison of presenilin 1 and presenilin 2 γ-secretase activities using a yeast reconstitution system (2011)
  • Author(s): Yonemura, Y., Futai, E., Yagishita, S., Suo, S., Tomita, T., Iwatsubo, T. & Ishiura, S
  • Journal Title: J. Biol. Chem Volume: 286 Pages: 44569-44575
  • Peer Reviewed
• [Journal Article] Comparison of presenilin 1 and presenilin 2 γ-secretase activities using a yeast reconstitution system. (2011)
  • Author(s): Yonemura, Y., Futai, E., Yagishita, S., Suo, S., Tomita, T., Iwatsubo, T. & Ishiura, S.
  • Journal Title: J. Biol. Chem. Volume: 286 Pages: 44569-44575
  • Peer Reviewed
• [Presentation] プレセニリンとAph1 分子の違いがγセクレターゼの機能に及ぼす影響 (2013)
  • Author(s): 米村洋而, 二井勇人, 柳下聡介, 石浦章一
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸
  • Year and Date: 2013-12-05
• [Presentation] 酵母再構成系を用いたγセクレターゼの機能解析 (2013)
  • Author(s): 米村洋而, 二井勇人, 柳下聡介, 周防諭, 石浦章一
  • Organizer: 第17回病態プロテアーゼ学会学術集会
  • Place of Presentation: 浜松
  • Year and Date: 2013-08-10
• [Presentation] プロリン異性化酵素Pin1 はPresenilin に結合し, 活性を制御する (2013)
  • Author(s): 佐々木広美, 二井勇人, 内田隆史
  • Organizer: 2013年度日本農芸化学会大会
  • Place of Presentation: 仙台
  • Year and Date: 2013-03-25
• [Presentation] 酵母再構成系を用いたγセクレターゼの機能解析 (2013)
  • Author(s): 米村洋而、二井勇人、柳下聡介、周防諭、石浦章一
  • Organizer: 第17回病態プロテアーゼ学会学術集会
  • Place of Presentation: オークラアクトシティホテル浜松
• [Presentation] プレセニリンとAph1分子の違いがγセクレターゼの機能に及ぼす影響 (2013)
  • Author(s): 米村洋而、二井勇人、柳下聡介、石浦章一
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド
• [Presentation] プロリン異性化酵素Pin1はPresenilin1に結合し、活性を制御する (2013)
  • Author(s): 佐々木広美、二井勇人、内田隆史
  • Organizer: 2013年度日本農芸化学会大会
  • Place of Presentation: 仙台市
• [Presentation] 酵母再構成系によるγセクレターゼ活性の評価 (2012)
  • Author(s): 米村洋而, 二井勇人, 柳下聡介, 周防諭, 石浦章一
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
  • Year and Date: 2012-12-14
• [Presentation] エタノールアミン型リン脂質のγセクレターゼのin vitro 活性への影響 (2012)
  • Author(s): 小野寺智子, 佐々木広美, 二井勇人, 内田隆史, 神尾好是, 金子淳
  • Organizer: 2012年度日本農芸化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2012-03-25
• [Presentation] 酵母再構成系によるγセクレターゼ活性の評価 (2012)
  • Author(s): 米村洋而、二井勇人、柳下聡介、周防諭、石浦章一
  • Organizer: 第３５回日本分子生物学会
  • Place of Presentation: 福岡市
• [Presentation] 酵母再構成系によるγセクレターゼにおけるPS1とPS2 の比較 (2011)
  • Author(s): 米村洋而, 二井勇人, 柳下聡介, 周防諭, 富田泰輔, 岩坪威, 石浦章一
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-15
• [Presentation] γセクレターゼによるAβ生成へのPin1 の作用機構解析 (2011)
  • Author(s): 佐々木広美, 内田隆史, 二井勇人
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-14
• [Book] 脳-分子・遺伝子・生理- (2011)
  • Author(s): 石浦章一, 笹川昇, 二井勇人
  • Publisher: 裳華房